In pharmacological research on hypertension, recent attention has focused on the study of the renin-angiotensin-aldosterone system, and, in particular, on the development of an effective anti-hypertensive agent which would, theoretically, achieve its result by inhibiting the action of angiotensin converting enzyme in converting angiotensin I to angiotensin II. The inhibition of the production of angiotensin II became important because of the discoveries that angiotensin II is the most potent pressor agent (vasoconstrictor) present in the mammalian body and, in addition, stimulates the adrenal cortex to release aldosterone, thereby causing excessive sodium retention and fluid retention, contributing further to the hypertensive state. Thus, inhibiting the conversion of angiotensin I to angiotensin II is believed to work directly on the primary biochemical mechanisms creating increased blood pressure. For a description of the mechanisms and of the mammalian renal-angiotensin-aldosterone system, see Hypertension, Genest et al., ed., Chapters 6.2 and 7.3 (McGraw-Hill, 1977) and John H. Laragh, "The Renin System in High Blood Pressure, From Disbelief to Reality: Converting-Enzyme Blockade for Analysis and Treatment", Prog. in Cardio. Vasc. Disease, XXI, No. 3, 159-166 (November, 1978).
As described by Suzanne Oparil in Genest et al., supra, Chapter 6.3, two of the most potent and most studied inhibitors of angiotensin converting enzyme are the Bothrops jararaca snake venom extracts, the pentapeptide (Pyr-Lys-Trp-Ala-Pro), also referred to as BPP.sub.5a, and the nonapeptide (Pyr-Trp-Pro-Arg-Pro-Gln-Ile-Pro-Pro), also referred to as BPP.sub.9a. (BPP stands for Bradykinin Potentiating Peptide). BPP.sub.9a has been shown to be an effective anti-hypertensive agent in clinical studies on humans with certain forms of hypertension. However, BPP.sub.9a is not orally active as an anti-hypertensive agent. For a summary of the clinical aspects of BPP.sub.9a see Genest et al., supra, Chapter 6.3, pp. 163-4.
Such studies led to the development of a series of proline derivatives which were significantly more potent as inhibitors of angiotensin converting enzyme and as anti-hypertensive agents than BPP.sub.9a. Of these proline derivatives, D-3-mercapto-2-methylpropanoyl-L-proline has been reported to be the most effective, including being effective when administered orally. These proline and mercaptoproline derivatives and various pharmacological test results thereon are described in Cushman et al., "Design of New Anti-hypertensive Drugs: Potent and Specific Inhibitors of Angiotensin Converting Enzyme", Prog. in Cardio. Diseases, Vol. XXI, No. 3 (Nov./Dec., 1978), and in U.S. Pat. Nos. 4,046,889 (a) and 4,105,776 (b), both to Ondetti and Cushman.
Subsequently, other proline derivatives and various pipecolic acid and thiazolidinecarboxylic acid derivatives were also disclosed as having angiotensin converting enzyme (ACE) inhibition and anti-hypertensive properties in the following publications:
(c) U.S. Pat. No. 4,237,134, dated Dec. 2, 1980, to Ondetti;
(d) Belgium Brevet D'Invention No. 868,532, published Oct. 16, 1978, to Yoshitomi Pharmaceutical Industries, Ltd. (also United Kingdom Patent Specification No. 2,000,508);
(e) Derwent Abstract No. 22968 C/13 of Japanese Kokai No. 55022-673, published Feb. 18, 1980, to Yoshimoto Pharmaceutical Industries, Ltd.;
(f) Derwent Abstract No. 15734 C/09 of Japanese Kokai No. 550009-060, published Jan. 22, 1980, to Yoshimoto Pharmaceutical Industries, Ltd.;
(g) German Offenlegungsschrift No. 29 34 592, published Mar. 20, 1980, to American Cyanamid Co.;
(h) European Patent Publication No. 0012401, published June 6, 1980, to Merck & Co.; and
(i) Belgium Brevet D'Invention No. 872,972, published June 21, 1979, to Science Union et cie, Societe Francaise de Recherche Medicale.
Further, indoline and quinoline carboxylic acid derivatives having angiotensin converting enzyme inhibition and antihypertensive properties are described in the following:
(j) German Offenlegungsschrift No. 29 37 779, published Apr. 9, 1981, to Hoechst AG;
(k) U.S. Pat. No. 4,303,583, issued Dec. 1, 1981, to D. H. Kim et al.;
(l) U.K. Patent Application No. 2,027,025, published Feb. 13, 1980, to Santen Pharmaceutical Co., Ltd., and
(m) U.S. Pat. No. 4,284,561, issued Aug. 18, 1981, to Petrillo et al.
These references disclose pyridines, thiazolidines, and indolines, among others, substituted at the 2 position with carboxylic acids or esters and amides. EPC Pub. No. 0012401 (g) and Belgium Brevet D'Invention No. 872,972 (h), above, additionally disclose amides at the 2 position which are substituted on the amino group thereof by one or two alkyl groups, an hydroxy group, or a benzyl group, or the 2-carbonyl group is substituted with an "acylamino alkoxy" group. U.S. Pat. No. 4,284,561 (m) also discloses hydroxamic acids. Such substituents are unrelated to the alkylsulfonylamino substituents of the present invention.